A new system for continuously quantitating scratching activity, independent of gross limb movements, has been devised. This system permits objective quantitative studies of the effectiveness of therapies for the pruritus of cholestasis to be undertaken. Using this system naloxone infusions have been shown to decrease a scratching activity index by about 50% in patients with pruritus due to primary biliary cirrhosis, suggesting that the opiate system may be implicated in the mediation of the pruritus of cholestasis. Support for the hypothesis that the status of the opiate system is altered in cholestasis has been provided by showing that rats with acute cholestasis due to bile duct resection exhibit antinociception (as assessed by the tail flick assay) and that this pathophysiologic state can be stereoselectively reversed by naloxone. Furthermore, increased levels of total opioid activity and methionine enkephalin have been demonstrated in plasma in this model of cholestasis. These findings are consistent with the syndrome of cholestasis being associated with increased opiatergic tone mediated by endogenous opioids. As opiates, such as morphine, are known to induce pruritus, the mechanism of the pruritus of cholestasis could be increased opiatergic tone. A double blind trial of naloxone infusions for the pruritus of chronic cholestasis is nearing completion. An open trial of the orally bioavailable opiate antagonist nalmefene for this complication of cholestasis is also in progress. In six patients oral nalmefene was associated with a clinical amelioration of pruritus in all, an improvement in visual analogue scores in 5 and a decrease in scratching activity index in 4. In additional studies of the opiate system in cholestasis, bile duct resected rats have been shown to exhibit a naloxone- reversible decrease in the ACTH response to stress.